title: Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular antioxidant function.
abstract: Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1), expressed in HEK 293T cells and localized exclusively to membranes of the endoplasmic reticulum, was found to support both vitamin K 2,3-epoxide reductase (VKOR) and vitamin K reductase enzymatic activities. Michaelis-Menten kinetic parameters for dithiothreitol-driven VKOR activity were: K(m) (μM) = 4.15 (vitamin K(1) epoxide) and 11.24 (vitamin K(2) epoxide); V(max) (nmol·mg(-1)·hr(-1)) = 2.57 (vitamin K(1) epoxide) and 13.46 (vitamin K(2) epoxide). Oxidative stress induced by H(2)O(2) applied to cultured cells up-regulated VKORC1L1 expression and VKOR activity. Cell viability under conditions of no induced oxidative stress was increased by the presence of vitamins K(1) and K(2) but not ubinquinone-10 and was specifically dependent on VKORC1L1 expression. Intracellular reactive oxygen species levels in cells treated with 2,3-dimethoxy-1,4-naphthoquinone were mitigated in a VKORC1L1 expression-dependent manner. Intracellular oxidative damage to membrane intrinsic proteins was inversely dependent on VKORC1L1 expression and the presence of vitamin K(1). Taken together, our results suggest that VKORC1L1 is responsible for driving vitamin K-mediated intracellular antioxidation pathways critical to cell survival.
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, Sigmund-Freud-Strasse 25, University Clinic Bonn, 53127 Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Westhofen
authors.forename: Matthias
authors.initials: M
authors.lastname: Watzka
authors.forename: Milka
authors.initials: M
authors.lastname: Marinova
authors.forename: Moritz
authors.initials: M
authors.lastname: Hass
authors.forename: Gregor
authors.initials: G
authors.lastname: Kirfel
authors.forename: Jens
authors.initials: J
authors.lastname: Müller
authors.forename: Carville G
authors.initials: CG
authors.lastname: Bevans
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Müller
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide; D042541:Intracellular Space / Q000378:metabolism; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D021122:Protein Subunits; D010837:Vitamin K 1; D064417:Vitamin K Epoxide Reductases
chemical_list: D000975:Antioxidants; D021122:Protein Subunits; D010837:Vitamin K 1; D006861:Hydrogen Peroxide; D006899:Mixed Function Oxygenases; C531327:VKORC1L1 protein, human; D064417:Vitamin K Epoxide Reductases